Efficacy Of Recombinant Factor VII Research Articles

Safety and Efficacy of Recombinant Factor VIIa (NovoSeven) Use during ECMO Support in Patients after Cardiac Surgery

Background: Acute postoperative bleeding in cardiac surgical patients is a major cause of morbidity and mortality. Substitution of coagulatory factors may not always provide optimal hemostasis and off label, use of recombinant FVIIa has been proposed. When on ECMO, extra care must be taken during coagulatory substitution as clotting of the system may cause cardiovascular complications and possible ECMO failure, leading to death. In this paper, we examined the safety and efficacy of rFVIIa during ECMO support in postoperative cardio-surgical patients. Methods: We retrospectively examined all patients receiving rFVIIa postoperatively from December 2005 and January 2020. Clinical characteristics, demographics, bleeding, thrombotic complications, mortality, and rFVIIa administration were analyzed. Results: A total of 74 patients received rFVIIa postoperatively due to uncontrollable bleeding after cardiac surgery on our ICU. Of these patients, 23 patients were on ECMO treatment. Twelve patients received rFVIIa during, but not prior to the initiation of ECMO therapy. Six patients (50%) were male; mean age was 46 years (30-72 years). Eleven patients (91.7%) were on venoarterial ECMO, one patient was on central ECMO (8.3%). Dose of administered rFVIIa was corrected for body weight; mean dosage was 82μg/kg. We saw a significant reduction in need for red packed cells, fresh frozen plasma and thrombocyte transfusion after rFVIIa administration. There was no impact on the functionality of the ECMO system, especially regarding the oxygenator after rFVIIa administration. One patient suffered a stroke due thromboembolism (8.3%). One patient developed late thromboembolism in the leg (8.3%), and two cases of pulmonary embolism (16.7%) were recorded. Overall survival was 25% and there was no significant difference in survival between ECMO and non-ECMO patients. Weaning from ECMO could be achieved successfully in 41.7% of our patients. Conclusion: Recombinant Factor VIIa is an effective agent in reducing blood loss during ongoing ECMO therapy in patients with refractory bleeding. Although no direct relation between rFVIIa application and thromboembolic events could be established, its use should be done with the utmost care and in selected patients. However, rFVIIa therapy did not impact ECMO function in our cohort.

Safety and Efficacy of Recombinant Factor VII in HeartMate 3 Recipients

Safety and Efficacy of Recombinant Factor VII in HeartMate 3 Recipients

Efficacy of recombinant factor VIIa for severe bleeding complicated by platelet transfusion refractoriness in patients with hematologic malignancies

IntroductionSevere bleeding with platelet transfusion refractoriness (PTR) is a common complication associated with reduced survival in patients with hematologic malignancies. The present study aimed to evaluate the efficacy of recombinant factor VIIa (rFVIIa) for severe bleeding complicated by PTR. Materials and methodsSixty-four patients suffering from severe bleeding with PTR hospitalized in our center between September 2012 and December 2016 were enrolled in this study. Thirty-two patients received rFVIIa (rFVIIa group) and other conventional hemostatic treatments, while the other 32 patients received conventional hemostatic treatments other than rFVIIa (control group). ResultsThe baseline parameters of patients before treatment were similar in both groups. The total response rates to hemostatic treatment at 24h and 48h were significantly higher in the rFVIIa group compared with the control group (p=0.014, p=0.020, respectively). Significantly more patients in the rFVIIa group achieved complete responses (CR) at 24h (p=0.031), 48h (p=0.039), and 72h (p=0.021) compared with the control group. The bleeding score (p=0.029), time to control bleeding (p=0.034), and activated partial thromboplastin time (p=0.021) after hemostatic treatment were significantly lower in the rFVIIa group compared with the control group. Patients who achieved a CR to rFVIIa had a significant survival advantage compared with those with a partial response/no response (p=0.020). No complications with venous or arterial thromboembolism were observed during treatment. ConclusionsrFVIIa may provide effective and safe hemostasis in patients suffering from severe bleeding and PTR.

Safety and efficacy of recombinant factor VIIa by pediatric age cohort: reassessment of compassionate use and trial data supporting US label.

The relative safety and efficacy of recombinant activated coagulation factor VII (rFVIIa, NovoSeven® RT) across pediatric age cohorts is poorly defined. The objective of this analysis was to assess the safety and efficacy of rFVIIa in pediatric patients with congenital hemophilia with inhibitors (CHwI) in the clinical studies supporting the U.S. labeling. Pediatric data were derived from seven studies (five acute and two perioperative treatments) and pooled. All data were stratified by age (<2, 2 to <6, 6 to <12, and 12-16 years) and study category (acute treatment of bleeding episodes or surgery). The pediatric dataset included 172 patients; 144 received rFVIIa for the treatment of bleeding episodes and 28 for the control of bleeding perioperatively. Recombinant FVIIa was effective for 95.4% (1,026/1,076) of the evaluable bleeding episodes and had similar treatment effectiveness across pediatric age groups (range, 94.1-97.2%). The majority received doses of 90 mcg/kg. rFVIIa was effective in achieving perioperative hemostasis across pediatric age groups (range, 91-100%), with greater efficacy observed with the recommended (90 mcg/kg) versus lower dose (35 mcg/kg). A total of 88 pediatric patients experienced a total of 285 adverse drug reactions, similar in type to those reported among adult patients. A total of seven thrombotic events were recorded in seven pediatric patients; only one was confirmed related to rFVIIa upon individual case review. rFVIIa is safe and effective in the treatment of bleeding episodes and prevention of periprocedure bleeding in CHwI with no apparent differences observed among pediatric age groups.

Safety and Efficacy of Recombinant Factor VIIa (rFVIIa) in Congenital Hemophilia with Inhibitors (CHwI) in the Home Treatment Setting: Systematic Review of Clinical Studies and Registries

Background: The FDA approved rFVIIa (NovoSeven®RT) in 1999 for treatment of CHwI patients (pts) and it has been studied in compassionate/emergency use programs, clinical trials, and registries for nearly 30 years in this indication. US prescribing information directs that initially, treatment should be instituted under supervision of a physician. While home treatment is common in hemophilia including patients with inhibitors in clinical studies, scientific publications often omit the treatment location. Recent information requests in relation to policy decisions by payers around home use of rFVIIa prompted systematic analysis of clinical studies and registries where predominant use was in the home setting.Aim: To analyze rFVIIa safety and efficacy data in home treatment in clinical trials and registries.Methods: A systematic review focusing on the efficacy and safety of rFVIIa for the management of congenital hemophilia A and B patients with inhibitors in the home setting was performed. Studies included in the review consisted of clinical trials (phase I-IV) and prospective and retrospective registries evaluating bleed management and prophylaxis.Results: A detailed review identified 14 studies for treatment of bleeding (3 phase II, 2 phase III, 9 phase IV) in the home setting including studies reporting on standard doses (90 mcg/kg), high single doses (270 mcg/kg), and observational studies (dosing per physician direction). These studies captured 865 patients treated for 9,024 bleeding episodes (see Table 1), including 640 patients with 6,999 episodes in studies where efficacy was evaluable. Efficacy was consistently high across studies. The 10-year Japanese post-marketing study (F7HAEM-1947) required all adverse events to be reported irrespective of causality; one patient had visual field defect and suspected cerebral infarction, one central venous occlusion, and two others had events that are not clearly thrombotic (hemolytic uremic syndrome, acute renal failure). The only thromboembolic event (TE) reported in phase II-III studies was in 1 patient in the phase II adept™2 trial, which compared vatreptacog alpha with rFVIIa. Apart from the Japanese study, thrombotic rate was 1/7306 bleeds (0.014%).Table 1On demand treatment of bleeding with rFVIIaTrial IDPhaseNumber of PatientsNumber of BleedsEfficacySafetyF7HAEM-1510II224288%No TEF7HAEM-2068II244591-92%No TENN7128-1907 (Pioneer 1)II2335984%No TEF7HT/USA/1/USA (US Home Trx)III5687792%No TENN1731-3562 (adept™2)III5722793%1 TEHRS/HTRS Registry (2000-2003)IV4279387%No TEHTRS Registry (2004-2008)IV1292,04189-93%No TEF7HAEM-1965 (DOSE)IV35158Not assessed (diary)No TEF7HAEM-3507 (ONE)IV10249685-96%No TENN7025-3601 (SMART-7)IV51511Not reported (interim)No TEF7HAEM-3537 (UKHCDO Registry)IV1391,356Not reported (diaries)No TEF7HAEM-1947IV144*1,718*88%2TE†F7AHEM-1921 (WIRK Registry)IV1426990%No TEF7HAEM-3850IV2713281%-92%No TETotal8659,024* Patients with evaluable efficacy.† One visual field defect with suspected cerebral infarction, one central venous occlusion.Two studies evaluated rFVIIa for secondary prophylaxis (1 phase II, 1 phase IV) (see Table 2). The phase II study captured 22 patients treated with 90 or 270 mcg/kg daily. The phase IV retrospective study captured 86 patients with varied rFVIIa doses that often changed over time. Effective reduction in bleeding was seen in both studies. Across 108 patients treated with prophylaxis at home over 42,861 days, there were no thrombotic events reported.Table 2Secondary Prophylaxis with rFVIIaTrial IDPhaseNumber of PatientsNumber of Prophylaxis DaysEfficacySafetyF7HAEM-1505II221,88545-59% reductionNo TEF7HAEM-3695 (PRO-PACT)IV8640,97646-52%No TETotal10842,861Conclusions: Analysis of data from clinical studies of rFVIIa in home treatment of bleeding and secondary prophylaxis of bleeding demonstrates consistent efficacy for treatment and prevention of bleeding. Thrombotic events were uncommon across ~9,000 bleeding episodes and not reported in ~43,000 prophylaxis days. These data support the safety and efficacy of rFVIIa in the home treatment setting and sufficient evidence for payers to continue its approval in the home management of hemophilia patients. DisclosuresYoung:Kedrion: Consultancy; Bayer: Consultancy; Baxter: Consultancy; Biogen Idec: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria. Escobar:Novo Nordisk Inc.: Consultancy; Baxter: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Biogen: Consultancy; CSL Behring: Consultancy. Pipe:Biogen Idec Inc: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; American Thrombosis and Hemostasis Network: Other: Chair of the Board of Directors; National Hemophilia Foundation: Other: member of the Medical and Scientific Advisory Committee; Novo Nordisk: Consultancy; Baxter: Consultancy. Cooper:Novo Nordisk Inc.: Employment.

Postsurgical coagulopathy in a hemophilia A patient with inhibitors: efficacy of recombinant factor VIIa

Perioperative hemostatic management in patients with hemophilia A who develop the coagulation factor VIII (FVIII) inhibitor is challenging, because exogenous FVIII is neutralized, which boosts the inhibitor to provoke postoperative coagulopathy. Recombinant activated factor VII (rFVIIa) has become available for this type of patient, although FVIII is sometimes required. We treated a 56-year-old male patient with hemophilia A with FVIII inhibitor scheduled for total hip arthroplasty (THA) and total knee arthroplasty (TKA). We used rFVIIa for THA; however, the amount of bleeding was 2,500 ml and blood transfusion was required, which boosted FVIII inhibitor after surgery. The TKA was then scheduled for 19 months later, after the level of the inhibitor had reduced to the preoperative level. Unfortunately, rFVIIa failed to improve PT/APTT, and thus we used recombinant factor VIII (rFVIII). The amount of bleeding during TKA was 1,340 ml, while the level of the inhibitor increased to a greater level than that after THA, provoking uncontrollable bleeding. For anesthetic management in hemophilia A patients with FVIII inhibitor, anesthesiologists must pay attention to postoperative coagulopathy, and every effort should be used to minimize exposure to FVIII. Furthermore, when rFVIIa is ineffective, postponement of surgery until rFVIIa regains its efficacy may be beneficial as compared to an operation with FVIII.

Surgery in patients with haemophilia and high responding inhibitors: Izmir experience

This report evaluates the haemostatic efficacy of recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) in patients with haemophilia and high responding inhibitors who underwent major and minor surgery. Data pertaining to surgeries from 2001 to 2009 at a single centre were retrospectively analysed. During this period, 53 surgical procedures were performed in 30 haemophiliacs with high responding inhibitors. Mean age was 16.2±9.4 years. Eleven major surgeries in 4 patients, 41 radioisotope synovectomies (RS) and one circumcision classified as minor surgery in 28 patients were performed. Among the major surgery procedures, four were treated with rFVIIa, five with APCC and two with sequential use of APCC and rFVIIa. We used rFVIIa at the dosage of 80-120 μg kg(-1) every 2 h and APCC 100 IU kg(-1) every 12 h for the major surgery. When performing RS, we used rFVIIa in 18 patients with 26 target joints and APCC in 9 patients with 15 target joints. Three consecutive doses of rFVIIa (90 μg kg(-1) ) were used at 2-h intervals followed by additional three doses at 6-h intervals. The initial dose of APCC was 75 IU kg(-1) followed by a second and third dose of 50 IU kg(-1) at 12-h intervals. APCC and rFVIIa demonstrated excellent efficacy in our major and minor surgical interventions [100% (22/22) and 94% (31/33), respectively]. We had only two bleeding complications with rFVIIa. There were no thromboembolic complications. APCC and rFVIIa provide an effective and safe first line haemostatic therapy for inhibitor-positive haemophiliacs, allowing both major and minor surgery to be successfully performed.

Variability of thromboelastographic responses following the administration of rFVIIa to haemophilia A dogs supports the individualization of therapy with a global test of haemostasis

The efficacy of recombinant factor VIIa (rFVIIa) therapy in haemophilia A is challenged by the lack of a reliable monitoring tool for treatment response. This is further complicated by the significant inter-patient variability associated with this response. Thromboelastography (TEG), a real time global haemostatic test has shown superiority over conventional tests of haemostasis and has proven efficiency in the monitoring of bypass agents such as rFVIIa and FEIBA™. However, this evaluation has been limited to a few case studies or very small patient series. In this study, six severe haemophilia A dogs were treated with a clinically relevant single dose of rFVIIa, and therapy was monitored by thromboelastography predrug and at 15, 30 and 60 min postdrug administration using citrated whole blood samples activated with tissue factor and compared with non-tissue factor-activated samples. Despite the homogeneity of the tested dogs, a clear inter-individual variation was observed in the pre-and post-rFVIIa Thromboelastography analyzes. The improvement of global haemostatic parameters was seen as early as 15 min following drug administration, with a peak for factor VIIa activity in plasma at the same time. There is a significant correlation between plasma FVIIa and TEG parameters 15 min postinjection, and the baseline TEG profile influences the individual postdrug administration outcome. Together, these data support the value of TEG not only as an effective monitoring haemostatic test, but also as a tool for individualization of therapy to achieve the best haemostatic and cost effectiveness of rFVIIa therapy.

Animal models of FVIIa gene expression: their role in the future development of haemophilia treatment

The development of inhibitors to replacement factor therapy is a serious complication in the treatment of patients with haemophilia and requires use of bypassing agents to prevent uncontrolled bleeding. The efficacy of recombinant factor VIIa (rFVIIa) as a bypassing agent in patients with haemophilia has been demonstrated in case studies and clinical trials. However, the perception of a short plasma half-life and consequent need for repeated daily injections means that long-term prophylaxis could potentially be limiting. Canine haemophilia models using a gene transfer approach have been used to evaluate the continuous expression of FVIIa in dogs. These studies show improvement in measurable bleeding parameters that have important clinical ramifications for patients with haemophilia. The combination of gene transfer as the method of delivery and FVII as the transgene overcomes issues associated with the short plasma half-life of rFVIIa, and represents a potentially attractive novel approach to haemostasis in patients with haemophilia and other platelet disorders.

Clinical and echographical control protocol of haemarthrosis in haemophilia patients with inhibitors: evaluation of the efficacy of recombinant factor VIIa in the evolution process (EFFISEVEN protocol)

The intention of the 'clinical and echographical protocol of evaluation the efficacy of recombinant activated factor VII in the haemarthrosis' (EFFISEVEN protocol) was to provide an extensive study of the evolution of haemarthrosis, and second, of its repercussions on the degenerative process of joints. The clinical evaluation of haemarthroses and their evolution is based on a well-established methodology, although very few studies have sought to determine the correlation between pain, mobility and the objective data regarding the haemorrhage. We believe that it is necessary to unify criteria and that the EFFISEVEN protocol may contribute data that improve standards which, in turn, will influence the degenerative process of joints, and consequently affect the quality of life of haemophilia patients with inhibitors. Echographical control of haemarthrosis is an objective method that allows control over how the haemorrhage evolves and also helps in the identification of rebleeding. Therefore, its use adds a new dimension to patient management strategies. Techniques used to monitor recombinant activated factor VII (rFVIIa) treatment require further study, although preliminary results guarantee their efficacy.

Recombinant factor VIIa for warfarin-associated intracranial bleeding

Study objective To examine the efficacy of recombinant factor VIIa (rVIIa) in reversing warfarin-induced coagulopathy in trauma patients presenting with intracranial hemorrhage (ICH). Design Retrospective, cohort-controlled database review. Setting Level 1, university-affiliated trauma center. Patients 54 patients presenting with ICH associated with chronic warfarin therapy, 30 of whom were treated with rVIIa, and the other 24 patients treated conventionally. Measurements We examined initial and subsequent coagulation studies (prothrombin time, international normalized ratio [INR]), blood product requirement, and clinical outcome, including time to reverse anticoagulation, duration of reversal, and subsequent mortality. Main results Patients treated with rVIIa required significantly less plasma (4 vs 7 units) to correct their INR, and corrected in a much shorter period of time (2.4 vs10 hrs). The duration of corrected INR after rVIIa was dose-dependent. Conclusions Factor rVIIa provides prompt correction of the INR of dose-dependent duration in patients with ICH intracranial hemorrhage associated with warfarin use.

Activated Recombinant Factor VII in Orthotopic Liver Transplantation

Orthotopic liver transplantation (OLT) is affected by important alterations of hemostasis. The aim of this study was to evaluate the efficacy of recombinant factor VII activated (rFVIIa) to reduce intraoperative bleeding during OLT. Methods Twenty OLT patients were assigned in double-blind way to a rFVIIa group or a control group. Inclusion criteria were hemoglobin > 8 g/dL: INR > 1,5 and fibrinogen > 100 mg/dL. We administered a single bouls of rFVIIa (40 μg/kg) or placebo. We determined INR, partial thromboplastin time, fibrinogen, ATIII, and blood cell counts. Blood products were administered as follows: 4 units of fresh frozen plasma when INR > 1.5, and 1 unit of RBC for Hb < 10 g/dL. The study ended 6 hours after the bolus. Results No thromboembolic events occurred. The INR was different between rFVIIa group and the controls at T0 (1.9 vs 1.6 P < .021) and during T1 (1.2 vs 1.6 P < .004). The total transfused red blood cells was 300 mL ± 133 in rFVIIa group and 570 mL ± 111 in control group ( P < .017). The total fresh frozen plasma was 600 mL ± 154 in rFVIIa group and 1400 mL ± 187 in control group ( P < .001). Total blood loss was greater in the control group than the rFVIIa group: 1140 mL ± 112 vs 740 mL ± 131 ( P < .049). Discussion The use of rFVIIa during OLT can reduce the risk of bleeding during surgery. The literature has described cases who did not benefit from the treatment. An adequate cut-off of INR, allowed us to treat only patients at greater bleeding risk.

A study of blood product use in patients with major trauma in Scotland: analysis of a major trauma database

Objectives: (1) To define blood product requirements in patients with trauma whose underlying injuries are consistent with major blood loss; (2) to use these data to estimate the annual number...

Recombinant Factor VIIa (Eptacog Alfa)

Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is indicated as an intravenous haemostatic agent in haemophilia patients with inhibitors to clotting factors VIII or IX. In noncomparative trials in haemophilia patients with inhibitors, on-demand home treatment with recombinant factor VIIa was effective in controlling episodes of mild to moderate bleeding and well tolerated, with early treatment being associated with a greater rate of success and the need for fewer doses than delayed treatment. Prophylactic treatment with recombinant factor VIIa was also effective in maintaining haemostasis in patients with this indication undergoing surgery. Relative to prior treatment with plasma-derived agents, treatment with recombinant factor VIIa was associated with improvements in health-related quality of life in a cost-utility study in haemophilia patients with inhibitors in Australia. In well designed decision-model cost analyses conducted from a healthcare payer perspective in several countries, on-demand treatment with recombinant factor VIIa to control mild to moderate bleeding episodes in this patient population was predicted to be cost saving or cost neutral relative to on-demand treatment with intravenous activated prothrombin complex concentrate (aPCC). Although the acquisition cost of recombinant factor VIIa was greater than that of aPCC in some studies, the greater initial efficacy of recombinant factor VIIa than aPCC resulted in lower predicted total medical costs. Results were generally robust to plausible changes in key parameters. Orthopaedic surgery with recombinant factor VIIa to maintain haemostasis in haemophilia patients with inhibitors was generally predicted to be cost saving, relative to not having surgery, over the medium to long term in modelled cost analyses from a healthcare payer perspective in the UK and US. The initial cost of surgery was high, but the difference in costs between patients undergoing or not undergoing surgery was predicted to decline over time, as savings were realised from the decrease in the number of bleeding episodes requiring treatment in patients who underwent surgery. In haemophilia patients with inhibitors, recombinant factor VIIa is clinically effective in controlling mild to moderate bleeds, and in maintaining haemostasis in patients undergoing orthopaedic surgery. Available pharmacoeconomic data from several countries, despite inherent limitations, support the use of recombinant factor VIIa as a treatment option that is at least cost neutral relative to aPCC in treating mild to moderate bleeds in this patient population. In addition, orthopaedic surgery with recombinant factor VIIa to maintain haemostasis in haemophilia patients with inhibitors is generally cost saving relative to not having surgery over the medium to long term, as the acquisition costs of recombinant factor VIIa are offset by cost savings resulting from the decrease in the number of joint-related bleeds.

The Role of Recombinant, Activated Factor VII in Hemorrhage Following Cardiac Surgical Procedures

SUMMARYWhile the usage of aprotinin and other antifibrinolytics has significantly decreased bleeding and transfusion requirements in cardiac surgical patients in general, certain patients still experience massive hemorrhage despite such therapy. Reexploration for bleeding has been identified as a strong independent risk factor for operative mortality, renal failure, prolonged mechanical ventilation, adult respiratory distress syndrome, sepsis, and atrial arrhythmias. Consequently, therapies to effectively limit otherwise uncontrolled hemorrhage have an important role in the clinical management of cardiac surgical patients. The hemostatic efficacy of recombinant factor VIIa (rFVIIa) appears to lie in its ability to activate FX directly to produce thrombin, independent of the presence and/or activity of co‐factors FVIII, FIX or FXI. There is also some evidence for the efficacy of rFVIIa in patients with platelet dysfunction which may also be relevant to its usage in cardiac surgical patients. This review considers the most recent clinical reports of the usage of rFVIIa for the control of massive blood loss and potentially fatal hemorrhage following cardiac surgery, with a view to assessing efficacy and dosing strategies. In addition, concern has been raised that patients undergoing cardiac surgery may have vulnerable plaques in coronary arteries or aorta, thus the risk of intracoronary activation of hemostasis with consequent potential for ischemic and thrombotic events may exist. Controlled clinical trials of rFVIIa assessing dose‐ranging and with adequate power to detect the impact of therapy on morbidity and mortality are necessary before it can be recommended for routine use in patients who present excessive bleeding following cardiac surgery.

Platelet-dependent thrombin generation assay for monitoring the efficacy of recombinant Factor VIIa

Although the administration of recombinant coagulation factor VIIa (rFVIIa) is a well established treatment in haemophilia with inhibitory antibodies, monitoring the therapeutic efficacy is still a problem. This is because the complete haemostatic effect in vivo depends on negatively charged surfaces provided by exposed lipids from activated platelets which are not present in standard clinical assays using plasma. The thrombin generation assay, however, measures the endogenous thrombin potential (ETP) in platelet-rich plasma (PRP) and this assay might be useful for monitoring the haemostatic response to rFVIIa. We characterized the in vitro concentration–response relationship of rFVIIa and the thrombin generation parameters ETP, PEAK and TIME TO PEAK using platelet-rich plasma (PRP) and rFVIIa at concentrations between one and five times the therapeutic dose. We also studied the effect of inhibiting tissue-factor and the intrinsic coagulation pathway using excess TF-neutralizing antibodies and corn trypsin inhibitor (CTI), respectively. There was a sigmoid relationship between ETP and PEAK and the dose of rFVIIa. Increasing rFVIIa concentrations between 100 and 500 U/ml resulted in a progressive increase in ETP, whereas supratherapeutical concentrations led to a plateau phase. The plateau phase differed between patients, suggesting a biological variation in the maximum ETP. Neutralization of plasma TF with TF-Ab partially decreased FVIIa efficacy. The inhibitory effect of CTI on rFVIIa-induced thrombin generation via the intrinsic pathway was negligible. The thrombin generation assay using PRP is a useful test for determining the sufficient efficacy of rFVIIa in blood. Once a plateau level is reached, higher doses of rFVIIa have no additional effect on haemostatic efficacy. The variation in plateau levels between subjects indicates that there are inter-individual differences in the level of thrombin activity that can be generated. High doses of rFVIIa are effective even in the absence of TF.

Recombinant Factor VIIa (Eptacog Alfa)

Recombinant factor VIIa (NovoSeven) [also known as recombinant activated factor VII or eptacog alfa] is a vitamin K-dependent glycoprotein that is structurally similar to human plasma-derived factor VIIa. It is a recombinant product, manufactured using DNA biotechnology. Intravenous recombinant factor VIIa has been evaluated in the treatment of bleeding episodes and for providing haemostasis cover during surgery in patients with certain bleeding disorders. Large, well controlled trials of recombinant factor VIIa have not been performed because of the rarity of these bleeding disorders. However, the efficacy of recombinant factor VIIa has been investigated in these patients in double-blind dose-finding or noncomparative clinical trials and worldwide compassionate-use programmes. Recombinant factor VIIa is effective and generally well tolerated in patients with haemophilia A or B with inhibitors, those with acquired haemophilia or Glanzmann's thrombasthenia. Also, recombinant factor VIIa is a treatment of choice in patients with haemophilia B with high-responding inhibitors and those with factor VII deficiency. Direct head-to-head comparisons and robust pharmacoeconomic data are required to fully determine the position of recombinant factor VIIa in relation to other therapies. Importantly though, the product appears to be relatively free of antigenicity, thrombogenicity and risk of viral transmission that, in the past, have limited the utility of blood products. Given that these characteristics are important determinants of the place of a treatment in bleeding disorders, recombinant factor VIIa provides a valuable treatment alternative in patients with haemophilia with inhibitors, platelet-refractory Glanzmann's thrombasthenia or congenital factor VII deficiency.

Recombinant factor VIIa to control excessive bleeding following surgery for congenital heart disease in pediatric patients.

The purpose of this article is to evaluate the efficacy of recombinant factor VII (rFVIIa) in the treatment of bleeding following cardiac surgery in a pediatric population. The study included a case series of postcardiac surgical patients with chest tube output of = 4 mL/kg/h for the initial 3 postoperative hours who received rFVIIa. Chest tube output for the 3 hours before and the 3 hours after rFVIIa was compared using a paired t test. In addition, chest tube output for the initial 3 postoperative hours and the 3 hours following rFVIIa was compared to 8 control patients who did not require rFVIIa. Recombinant factor VIIa was administered to 9 children (age = 9 +/- 4 years) following repair of tetralogy of Fallot (6), closure of ventricular septal defect (1), closure of sinus venosus atrial septal defect (1), and mitral valve repair (1). Chest tube output for the initial 3 postoperative hours prior to the administration of rFVIIa was 5.8 +/- 2.8 mL/kg/h and decreased to 2.0 +/- 1.3 mL/kg/h for the 3 hours following the administration of rFVIIa (P =.002). In the patients that did not receive rFVIIa, chest tube output for the first 3 postoperative hours was 1.6 +/- 0.9 mL/kg/h and 1.2 +/- 0.6 mL/kg/h for the next 3 hours (P = nonsignificant when compared to chest tube output for the 3 hours following rFVIIa in patients who received rFVIIa). No adverse effects were noted. Recombinant factor VIIa decreased chest tubing bleeding following cardiac surgery in children. Given its potential therapeutic impact, rFVIIa warrants further investigation in the pediatric cardiac population.

Safety of Recombinant Factor VIIa

SUMMARYRecombinant activated factor VII is an activator of blood coagulation that is highly effective as a hemostatic agent in patients with complicated hemophilia and other clotting disorders who experience major bleeding or need to undergo surgery. In recent years the potential of this agent to reduce perioperative bleeding and transfusion requirements in non‐hemophilia patients with excessive bleeding, for example after trauma or major surgical interventions, has been studied. Also, the use of recombinant factor VIIa to prevent bleeding and blood transfusion in patients who need to undergo invasive procedures that are associated with major blood loss has been investigated. Most of these observations and trials show efficacy of recombinant factor VIIa in reducing blood loss and the requirement for blood transfusion. Every prohemostatic intervention carries the risk of adverse events, in particular thrombosis. However, the initial reports show that adverse events due to recombinant factor VIIa are not frequent, although definitive conclusions regarding the safety of this approach should await larger trials.

Preliminary experience with the use of recombinant factor VIIa to treat coagulation disturbances in pediatric patients.

This study evaluates the efficacy of recombinant factor VII (rVIIa) in the treatment of coagulation dysfunction in pediatric patients. We retrospectively reviewed the records of pediatric patients who received rVIIa in the intensive care unit or operating room for treatment of coagulopathy. Case series in the literature were also reviewed. Ten patients, ranging in age from 3 months to 19 years, received 22 doses of rVIIa. Seven of the 10 patients had received fresh frozen plasma and cryoprecipitate before the administration of rVIIa without effect. All 10 patients had a fibrinogen level above 100 mg/dl and platelet count above 100,000/mm3 at the time of rVIla administration. After rVIIa administration, there were significant decreases in prothrombin time, international normalized ratio, and partial thromboplastin time. No adverse effects were noted. Recombinant factor VIIa can be used to effectively reverse coagulation disturbances in the pediatric patient even when treatment with fresh frozen plasma has failed. Given its therapeutic potential, prospective, randomized trials are warranted.